Targeted Therapies Could Be Key to Treating Myelodysplastic Syndrome


IDH inhibitors show encouraging results in patients with myelodysplastic syndrome, but longer follow ups are needed in a larger patient population to confirm the results.

Lionel Adès, MD, PhD, from the Hôpital Saint-Louis in Paris, France, discussed the need for more targeted approaches to myelodysplastic syndrome (MDS), during a presentation at the Society of Hematologic Oncology Annual Meeting 2022.

Adès opened the discussion by discussing unmet needs in higher-risk MDS and chronic myelomonocytic leukemia, adding that novel strategies and novel drugs are needed to address these patient populations.

Treatments for MDS can be targeted by different pathways, including methylation, neddylation, telomerase, Bcl2-related apoptosis, and similar pathways. Adès said that another approach is to target oncogenetic events in mutations associated with MDS oncogenesis, which was the area he focused on during the session.

He started by discussing 3 potential areas for targeted therapy: splicing gene mutations, TP53 mutation, and IDH1 and IDH2 mutations.

“[Splicing gene mutation] seems to be a quite promising target because they are quite frequent in patients with MDS and this is the most frequent mutating gene,” Adès said.

In a phase 1 trial (H3B8800), splicing showed very limited efficacy with 1 bone marrow response, and no complete or partial responses. However, investigators found that the SF3B1 mutation was associated with red blood count transfusion independence. The study is currently being extended for this population.

In targeting TP53 mutations, investigators found that the gene was detected in approximately 10% to 20% of individuals with de novo MDS or acute myeloid leukemia (AML), as well as in 30% to 40% of individuals with therapy-related diseases.

“The presence of TP53 mutation is usually associated with a very poor prognosis,” Adès said in the presentation.

Two trials being conducted in France and in the United States evaluated APR246, which was designed to re-conform TP53 mutations. Altogether, the overall response rate was 69%, with a complete remission rate (CRR) of 34%.

The median of overall survival was about 1 year, according to Adès. Additionally, another randomized study of APR246 in combination with azacytidine was conducted in individuals with TP53 mutant MDS. The trial failed to meet its primary endpoint of CRR.

Finally, Adès discussed IDH1 and IDH2 mutations, which are not as frequent for this patient population, with no more than 10% of individuals having these mutations.

He said that the IDH1 inhibitor ivosidenib and the IDH2 inhibitor enasidenib could be effective as either a single agent or in combination for a first-line therapy.

“In my group, we had the opportunity to evaluate both compounds, either ivosidenib or enasidenib, in 2 trials called IDIOME [IDH1] or IDEAL [IDH2],” Adès said in the presentation. “We treated patients in 3 different cohorts.”

Cohort A included patients with higher risk MDS who failed azacytidine. Cohort B also had patients with higher risk MDS who were treatment naïve and cohort C had patients with lower risk MDS who failed erythropoietin.

Cohort B was used as the first-line therapy group, with patients receiving 3 cycles of either drug every 28 days.

Cohort A had a 54% ORR, cohort B had a 91% ORR, and cohort C had a 50% ORR. Overall, 46% had a CRR and 94.4% achieved response at 3 cycles.

For IDH2 inhibitors, cohort B had an ORR of 56%, half of them being a CRR. Adès concluded that IDH inhibitors seemed to be effective and had encouraging results but need longer follow-ups and more individuals to confirm the results.

Splicing showed encouraging in vitro results, but clinical trials have only just begun for this method. For TP53 mutations, there were promising phase 2 data; however, the results were not conclusive for phase 3 studies, but subgroups may benefit from APR246.


Adès, L. Targeted Approaches in MDS. Society of Hematologic Oncology Annual Meeting 2022. September 28, 2022.

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